Simian immunodeficiency virus infection of rhesus macaques (Macaca mulatta) represents one of hte best available experimental models for human AIDS. In SIV infeciton a AIDS patients. In order to develop a reliable experimental model for neuropathological, behavioral, cognitive and pharmacologic studies of AIDS dementia complex we have initiated experiments to derive a neuroinvasive strain of SIV. By selection of virus populations replicating in brain derived microglial cells, we have demonstrated neuropathological changes in four of four infected macaques. Changes include perivascular and infiltrating mononuclear cells and multinucleate giant cells, viral gene expression, and host response. In the next project period we will continue to develop this model to enable us to probe the mechanisms and potential therapy of CNS alterations. Specific aims of this project include development and analysis of the pathologic effects of a neuroinvasive microglial cell derived stock of SIV, establishment of its growth characteristics and disease potential, and use of the neurovirulent stock to assess host and viral factors contributing to disease. LTR sequence control of replication in the macrophage/microglial cell lineage will be assessed as will the correlation between CNS viral titers and local cytokine production, host immune responses and pathological changes. Parameters of viral pathogenesis will be assessed in cohorts of behaviorally trained monkeys to establish correlation with pathology, temporality of measurement, cognitive change and host responses. Finally, a neurovirulent molecular clone of microglial adapted SIV will be derived in order to provide a stable benchmark for future cognitive and pharmacological studies, and to promote detailed studies of the mechanisms of pathogenesis of AIDS dementia.